Chemically-induced glutathione depletion and lipid peroxidation.
Malondialdehyde (MDA) formation in mouse liver homogenates was measured in the presence of various glutathione depletors (5 mmol/l). After a lag phase of 90 min, the MDA formation increased from 1.25 nmol/mg protein to 14.5 nmol/mg in the presence of diethyl maleate (DEM), to 10.5 with diethyl fumarate (DEF) and to 4 with cyclohexenon by 150 min. It remained at 1.25 nmol/mg with phorone and in the control. On the other hand, glutathione (GSH) dropped from 55 nmol/mg to 50 nmol/mg in the control to, less than 1 with DEM, to 46 with DEF, to 3 with cyclohexenon and to 7 with phorone. The data show that the potency to deplete GSH is not related to MDA production in this system. DEM stimulated in vitro ethane evolution in a concentration-dependent manner and was strongly inhibited by SKF 525A. From type I binding spectra to microsomal pigments the following spectroscopic binding constants were determined: 2.5 mmol/l for phorone, 1.2 mmol/l for cyclohexenon, 0.5 mmol/l for DEM and 0.3 mmol/l for DEF. In isolated mouse liver microsomes NADPH-cytochrome P-450 reductase and NADH-cytochrome b5 reductase activity were unaffected by the presence of DEM, whereas ethoxycoumarin dealkylation was inhibited. Following in vivo pretreatment, hepatic microsomal electron flow as determined in vitro was augmented in the presence of depleting as well as non-depleting agents, accompanied by a shift from O2- to H2O2 production. It is concluded that it is not the absence of GSH which causes lipid peroxidation after chemically-induced GSH depletion but rather the interaction of the chemicals with the microsomal monoxygenase system.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D003512:Cyclohexanones / Q000494:pharmacology; D003579:Cytochrome Reductases / Q000378:metabolism; D042966:Cytochrome-B(5) Reductase; D004980:Ethane / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology; D050356:Lipid Metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors; D011335:Proadifen / Q000494:pharmacology
D003512:Cyclohexanones; D005650:Fumarates; D007659:Ketones; D008298:Maleates; D008315:Malondialdehyde; C035088:diethyl fumarate; C018637:phorone; D011335:Proadifen; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase; D009251:NADPH-Ferrihemoprotein Reductase; C014476:diethyl maleate; D005978:Glutathione; D004980:Ethane